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Improving patient safety often involves multifaceted interventions intended to change complex workflows. This prospective cohort study examined whether a collaborative improvement initiative across 33 pediatric hospitals could augment patient safety. Hospitals volunteered to be part of the collaborative and paid an annual fee to participate. All but one submitted their safety data for inclusion in the study. The intervention involved identification and dissemination of evidence-based practices to reduce hospital-acquired conditions and prevent serious adverse events. Each hospital implemented these best practices locally according to their preferences. The collaborative provided virtual and in-person training for patient safety processes, such as unit-based safety rounds, root cause analysis, and inclusion of patients and families on hospital committees. Rates of hospital-acquired conditions and serious adverse events declined over time during the 3-year study. Because there were no concurrent control hospitals, it is not clear whether these improvements can be attributed to the intervention. The authors conclude that participation in a learning collaborative can enhance patient safety.